Ticks are obligatory ectoparasites that feed on the blood of vertebrate hosts and often transmit pathogens, including bacteria, protozoa, and viruses. Tick-borne diseases cause huge economic losses in the animal industry as well as health risks to humans. The salivary secretions of ticks play an important role in blood feeding by modulating the host response. We propose to investigate the neural mechanisms controlling salivary secretion in the black-legged tick, Ixodes scapularis, one of the most important ticks in the northern U.S. in terms of its risk to human health. Our preliminary studies, combined with previous studies, led to hypotheses attempting to explain the major mechanism involved in salivary gland control. We hypothesize that myoinhibitory peptide (MIP) and SIFamide control dopamine biosynthesis in the salivary glands. Dopamine, as a paracrine signal synthesized and secreted from basally located cells in the salivary gland acini, activates apical epithelial cells and granular cells in the acini for salivary secretion. To test these hypotheses, three Specific Aims are proposed in this proposal. Specific Aim 1 is to identify and characterize the receptors for each SIFamide and dopamine in the salivary glands. Specific Aim 2 is to investigate the biosynthesis of catecholamines in the salivary glands by biochemical analyses. Specific Aim 3 will be to investigate the functions of MIP, SIFamide, and dopamine signaling pathways in the salivary gland using RNAi and physiological assays. This study will contribute significantly to the body of knowledge that has accumulated in the last three decades with regard to the understanding of the mechanisms controlling the tick salivary gland. The fundamental knowledge obtained from this research is expected to lead to the design of compounds and vaccines that disrupt tick salivary function. The outcome of the proposed research will have a large impact on studies in other tick species that have negative impacts on the economy and human and animal health.